2014 Pipeline Report: The Sprint to Value

This year's pipeline report is a little different from reports in previous years in that it takes a closer look at fewer categories – the ones where the biggest things are happening: cancer, heart failure, obesity and diabetes, and hepatitis C, in addition to novel antibiotics, not a goldmine by any stretch, but an absolutely critical need. The last category, Outsiders, Sleepers, and Early Stagers, describes products that don't fit neatly into this year's setup, but are nevertheless worthy of mention. In October, a study in Nature Reviews Drug Discovery took pharma analysts to task for getting the numbers wrong—a lot—but we've endeavored to corroborate the forecasts, both bullish and bearish, and are confident that this year's report spotlights real value, for patients and bottomlines. The pharma business model might have changed, but a lot of companies have managed to hold on to their blockbusters.

Cancer: Multiple Targets

Genome-guided tumor diagnostics and treatments with the power to manipulate a patient's immune response have the potential to impact cancer outcomes in dramatic fashion. At the Cleveland Clinic's recent Medical Innovations Summit (see Pharm Exec's "Top Medical Innovations for 2014"), Eric Klein, chair at the Clinic's Glickman Urological & Kidney Institute, championed the work of companies like Genomic Health Inc.—and its recently CLIA-approved OncoType Dx prostate cancer assay—as critical to the future of cancer research and drug development. The genotype of a tumor may prove to be more useful than the genotype of the patient in which it resides. If identifying a "driver mutation" in metastatic cancers turns out to work in practice, it won't matter where a tumor originated in the body. Consequently, "drug development will be more rapid as a result," says Klein.

Designing clinical trials around a specific tumor mutation instead of a patient's cancer type probably won't start happening next year. In the shorter term, immunotherapies have maintained their buzz among researchers, with a spotlight on the role of Programmed Death-1 (PD1) as a way to cut off one important safe harbor for cancer cells looking to protect themselves from warring T cells. In addition to Bristol-Myers Squibb's nivolumab—which received FDA Fast Track designations in malignant melanoma, renal cell carcinoma and non-small cell lung cancer last April, Stephanie Hawthorne, director, clinical, and scientific assessment at Kantar Health, points to Merck's lambrolizumab and Roche's MPDL 3280A as key players in the PD1 game. Compared with nivolumab, Roche's MPDL 3280A (which targets the PD1 ligand—PD-L1—as opposed to the receptor) may have a better safety profile, while Merck's lambrolizumab may beat nivolumab on efficacy, although it's too early for excessive confidence on that prediction, says Hawthorne.

Lambrolizumab also received FDA's Breakthrough Therapy designation last April, and clinical trials are initially focused on melanoma and non-small cell lung cancer. Nivolumab is targeting melanoma and lung cancer, with the addition of renal cell carcinoma in Phase III. Merck announced plans to study lambrolizumab in other haematolgical malignancies, and has early trials running in triple negative breast cancer, colorectal cancer, bladder cancer, and other solid tumor cancers. Thompson Reuters' Cortellis database puts sales of lambrolizumab at roughly $845 million by 2018; Decision Resources' Efua Edusei made a similar prediction, around $800 million by 2019. "Merck would definitely have a better commercial opportunity if Yervoy wasn't already on the market," notes Edusea, adding that nivolumab could eventually restrict sales of lambrolizumab. With Zalboraf also looming large in the melanoma space, the initial label, launch date, and timeline for additional indications on both drugs could open or block the entrance to blockbuster fame and revenues. Roche is taking a different approach by shifting melanoma to the backburner; instead, MPDL 3280A is targeting the biomarker population in lung cancer as a lead indication. Merck followed suit with lambrolizumab, says Hawthorne. Thomson Reuters puts nivolumab sales at just over $2 billion by 2018; Decision Resources is more conservative on nivolumab, with sales just crossing the blockbuster mark by 2019.

In some ways, J&J/Pharmacyclics' ibrutinib takes a similar approach to treating cancer by inhibiting a normally protective pathway for infection-fighting B-cells. Like cancer cells hiding from T cell lymphocytes after corrupting the PD1 receptor pathway, the B-cell receptor pathway is corrupted when B-cells turn malignant. Ibrutinib inhibits the Bruton tyrosine kinase (BTK), which regulates B-cell survival. A first in class oral BTK inhibitor and an FDA Breakthrough Therapy designee, ibrutinib has filed with FDA for chronic lymphocytic leukemia (an orphan indication), and mantle cell lymphoma, also a rare disease. Achieving that rare double win—improved survival and reduced toxicity compared with chemotherapy—plus a fast track to market in the United States has prompted analysts to go big on ibrutinib. Estimates range from $3.5 (Thomson Reuters Cortellis) to $6 billion (Credit Suisse) by 2020.

In addition to ibrutinib are Gilead's idelalisib, a phosphoinositide-3 kinase (PI3K) inhibitor, and Rigel Pharmaceuticals' fostamatinib, a spleen tyrosine kinase (SYK) inhibitor. Both products, like ibrutinib, affect the B-cell pathway. Gilead filed idelalisib in the United States for a non-Hodgkin's lymphoma indication, and in October Rigel announced an end-of-Phase II meeting with FDA to discuss fostamatinib for immune thrombocytopenic purpura, or ITP (AstraZeneca ended its partnership with Rigel after the drug failed as a treatment for rheumatoid arthritis). Thomson Reuters is bullish on idelalisib, predicting sales of $3.8 billion, just short of projected ibrutinib sales. Hawthorne gives "a slight nod" to ibrutinib due to efficacy and safety; additionally, ibrutinib is pursuing a first-line indication in addition to second-line, whereas idelalisib is not currently in the clinic for a front-line indication. Roche/Biogen Idec's obinutuzumab, a CD20 inhibitor, is also a key product in this area; tested as a monotherapy and in combination with chemo for chronic lymphcytic leukemia, obinutuzumab also plays on the B-cell pathway, and also received FDA's coveted Breakthrough Therapy designation. Obinutuzumab was also granted priority review, and given a PDUFA date of December 20, 2013. Analysts are slightly less jazzed about obinutuzumab, at least compared with ibrutinib and idelalisib; forecasts from EvaluatePharma, Credit Suisse, and Thomson Reuters ranged from $400 million to around $750 million by 2019.

In breast cancer, palbociclib, a clinical candidate emerging from a research collaboration between Warner-Lambert (now Pfizer) and Onyx (now a subsidiary of Amgen), dazzled attendees of the San Antonio Breast Cancer Conference in 2012 with the results of a randomized Phase II trial. "It quadrupled progression-free survival," says Hawthorne. Currently in Phase III, palbociclib is being tested in combination with letrozole (brand name Femara, an aromatase inhibitor), and separately in combination with AstraZeneca's Faslodex (fulvestrant), to prove superiority over Faslodex alone. Edusei says several generic products in the hormone receptor positive (HR+) space, including letrozole, are available on the cheap, but palbociclib seems to represent a significant improvement over those products. Palbociclib targets metastic breast cancer in HR+ patients—more specifically, estrogen receptor positive (ER+)—that are also HER2 negative. HER2 positive breast cancer gets a lot of press, because of many new and successful drug targeting those patients, but hormone receptor positive patients are a much larger breast cancer population: roughly 75 percent of all breast cancer incidence is ER positive, according to the University of Maryland Medical Center. Thomson Reuters predicts blockbuster sales for palbociclib; Edusei and Decision Resources puts the number at $750 million by 2019.

Unfortunately, Eli Lilly had to can a 1,144 patient multinational Phase III study on ramucirumab, a VEGF antiangiogenic monoclonal antibody for breast cancer in September, but there's a silver lining. Ramucirumab received an FDA Fast Track designation for gastric cancer, and a Priority Review in October. Gastric cancer is a "high unmet need...if you can prolong survival, I think [Lilly] has a very good option for those patients," says Hawthorne.Interestingly, ramucirumab targets the VEGF receptor, whereas Avastin targets the ligand. Avastin failed in Phase III trials for gastric cancer, which raises the question: is there a true mechanistic difference in targeting the receptor versus the ligand? If so, "these angiogenics will start to separate themselves in terms of where they might be active," says Hawthorne. Sanofi/Regeneron haven't announced plans to test Zaltrap in gastric cancer, but http://ClinicalTrial.gov/ shows a Phase II study of Zaltrap for esophagogastric cancer, a malignancy in the throat as opposed to the stomach. Gastric cancer incidence in Japan has risen sharply in recent years; Decision Resources says the global gastric cancer market will reach $2.3 billion by 2021, with 44 percent of those revenues coming from Japan. Thomson Reuters pegs ramucirumab sales at $725 million by 2018, Leerking Swann says $1.3 billion by 2020.